Nitriloxy derivatives of (R) and (S)-carnitine

ABSTRACT

Carnitine derivatives of formula (I) are described in racemic and/or optically active form, as well as the process for their preparation and their use as pharmaceutical anti-angina active ingredients for the treatment of ischaemic heart disease.  
                 
 
     Also described is a process for producing the (R)-carnitine enantiomer from (S)-carnitine (or vice versa), using the derivatives of formula (I).

[0001] The invention described herein relates to derivatives of (R) and(S)-carnitine, and particularly nitriloxy derivatives which are usefulas intermediate synthesis products and as therapeutic agents.

BACKGROUND OF THE INVENTION

[0002] Organ ischaemia is caused by an imbalance between the oxygenrequirements of the tissue and oxygen availability from the bloodstream.In the particular case of cardiac ischaemia, this manifests with typicalsymptoms, known as angina pectoris. The causes are multiple and, amongthem, we should mention the reduced ability of the coronary circulationto supply oxygen, owing, for example, to the presence of atheromatousplaques. One possible consequence of the ischaemia is myocardialinfarction.

[0003] Myocardial ischaemia may also be asymptomatic and detectable onlyby means of clinical and instrumental examinations.

[0004] The therapy currently available is based mainly on theadministration of coronary dilating drugs, which, on account of thespecific needs of symptomatological treatment, have to have as rapid anaction as possible. Calcium antagonists, β-adrenergic antagonists andantiaggregant agents should also be mentioned.

[0005] Among the drugs still most commonly used today, we should mentionthe organic nitrates, which by releasing NO at the action site exert alocal vasodilatory action.

[0006] Amyl nitrite is used by inhalation in cases of angina attack.Nitroglycerine and organic nitrates of higher molecular weight are alsoused for the prevention of such attacks. Nitroderivatives are associatedwith a series of important side effects. The most common of these isheadache, which may even be very severe. More serious is the fact thatthese drugs give rise to tolerance and their withdrawal causes a reboundeffect. Nitroglycerine is also administered using transdermal releasesystems, which, however well designed they may be, present problems intheir own right, such as those relating to permanence at the applicationsite, controlled delivery of the drug and patient compliance.

[0007] Calcium antagonists present the problem of excessivevasodilatation, with consequent dizziness, hypotension, headache, andnausea, and it is by no means easy to establish the appropriatetherapeutic regimen.

[0008] β-antagonists have effects on cardiac haemodynamics.

[0009] For a more detailed discussion of these aspects, the reader isreferred to Goodman & Gilman's The Pharmacological Basis ofTherapeutics-9th edition, chapter 32.

[0010] To date, no single drug therapy is available for the treatment ofischaemic states, particularly angina pectoris, which possesses thedesired characteristics in terms of patient compliance, safety of use,lack of side effects and immediacy of action. In particular, no 5 esterof nitric acid is as yet available which combines the characteristics ofimmediacy of action and a lack of the side effects typical of this classof drugs.

[0011] Patent application Ser. No. W098/56759 describes pentaerythritederivatives of general formula (O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR¹)_(o)(COR¹)_(p). The multiple meanings of R¹ includenitriloxy derivatives of carnitine, in particular nitriloxy carnitinechloride, its inner salt and ester with(1-alkoxy-carbonylmethyl-2-trialkylammonium)ethanol. An ester of racemicnitriloxy-carnitine with (1-alkoxycarbonylmethyl-2-trialkyl-ammonium)ethyl alcohol is also envisaged, provided on mixtures containingequimolar amounts of (R) and (S) isomers. The anti-angina activity ofthese compounds is mentioned in the description.

[0012] Nitriloxy-carnitine is also prepared as an intermediate. Theexamples of the compounds are provided on the racemic mixtures. The onlyexample of a preparation, example 17, which uses L-carnitine, envisagesreaction with the chloride of3-nitriloxy-2,2-bis(nitriloxymethyl)propionic acid. The resultingcompound (not identified either in physico-chemical or in structuralterms) is not included in the claims and is not mentioned in relation toits presumed pharmacological activity. The patent application cited doesnot provide a general scheme for preparation of the compounds, and thusthe compounds effectively described are to be found in the preparationexamples. No pharmacological activity data are provided.

[0013] The action of L-carnitine in the treatment of heart failure isknown (U.S. Pat. No. 3,830,931).

[0014] Also known is the fact that acetyl L-carnitine enhances theoxidation of glucose and prevents the accumulation of lactate in theconcomitant acidosis (Lopaschuk, G. in Carnitine Today-C. De Simone andG. Famularo ed.) Lands Bioscience 1997).

[0015] Alkanoyl derivatives of L-carnitine are known for different usesin human or animal therapy.

[0016] It has now surprisingly been found that enantiomerically enrichednitriloxy derivatives of (R) or (S)-carnitine are endowed withfavourable and advantageous pharmacological activities, particularly astherapeutic agents for organ ischaemias, and even more particularly forthe treatment of angina pectoris.

[0017] Nitriloxy derivatives of (R) and (S)-carnitine are also usefulintermediates for synthesis for the production of chiral 3-4 carbon atomsynthons having the (R) or (S) configuration, such as for example3-hydroxy-γ-butyrolactone, 1,2,4-butantriole, 3-hydroxytetrahydrofurane,3-hydroxypyrrolidine, 2,3-dihydroxypropylamine, to be used in theindustrial synthesis of enantiomerically pure drugs. However, (R) and(S)-carnitine are not actually available at low cost, therefore aprocess convenient and applicable on a large scale, allowing thestereospecifica conversion of (S)-carnitine into (R)-carnitine orvice-versa will be economically advantageous and useful.

[0018] It has now surprisingly been found that enantiomerically enrichednitriloxy derivatives of (S)-carnitine, according to the presentinvention, are suitable intermediates for the production of(R)-carnitine e its derivatives, and vice-versa.

ABSTRACT OF THE INVENTION

[0019] The subject of the invention described herein are carnitinederivatives of general formula (I) in optically active form of absoluteconfiguration (R) or (S)

[0020] where

[0021] Y is an OR or NRIR2 group with

[0022] R equal to hydrogen, C₁-C₁₀ alkyl or alkyl substituted withC₆-C₁₀ (aryl, said aryl optionally carrying one or more C₁-C₄ alkyls;

[0023] R¹ and R², which may be the same or different, are hydrogen,C₁-C₁₀ alkyl or alkyl substituted with C₆-C₁₀ aryl, said aryl optionallycarrying one or more C₁-C₄ alkyls; or, taken together, form a 5-7 atomheterocyclic ring with the nitrogen atom;

[0024] or Y is the residue of an esterified polyalcohol with at leastone nitric acid equivalent;

[0025] X—is the anion of a pharmaceutically acceptable organic orinorganic acid,

[0026] or, if Y is an OH group, the formula (I) product may exist in theform of an inner salt, i.e. with structure (II)

[0027] and their enantiomerically enriched mixtures.

[0028] Examples of C₁-C₁₀ alkyls are methyl, ethyl propyl, butyl,pentyl, hexyl, octyl, nonyl, decyl and all their possible isomers.

[0029] Examples of substituted alkyls are benzyl and phenylethyl.

[0030] Examples of substituted aryls are tolyl, xylyl and its isomers.

[0031] Examples of polyalcohols are glyceryl mono- or dinitrate,isosorbide mononitrate, erythrityl di- o trinitrate, pentaerythritylmono-, di- or trinitrate.

[0032] Examples of anions of organic or inorganic acids are NO₃ ⁻, Cl⁻,Br⁻, I⁻, HSO₄ ⁻, (SO₄ ⁻⁻)_(0,5), H₂PO₄ ⁻, (HPO₄ ²⁻)_(0,5), (PO₄³⁻)_(0,33), a residue of a hydroxy acid, a residue of a bicarboxylicacid, OSO₂Z⁻, OCOZ⁻ or OCOH⁻ with Z equal to C₁-C₁₀ alkyl, substitutedalkyl, such as, for example, trihalomethyl or benzyl, aryl, such as, forexample, phenyl, tolyl, halophenyl or alkoxyphenyl. What is meant byhalogen is fluorine, chlorine, bromine and iodine. Preferred examples ofanions of organic and inorganic acids are those derived frompharmaceutically acceptable acids, among which, in addition to thoseexemplified above, we would mention particularly mandelate, orotate,acid aspartate, acid citrate, fumarate and acid fumarate, maleate andacid maleate, mucate, malate and acid malate, glucose phosphate,tartrate and acid tartrate, succinate, acid succinate, oxalate.

[0033] Examples of a heterocyclic ring with 5-7 nitrogen atoms aretetrahydropyrrhol, piperidine, piperazine, morpholine, alkyl-morpholineand azepine.

[0034] Compounds whose absolute configuration is (R) are preferred.

[0035] Additionally preferred are compounds whose absolute configurationis (R) and in which X⁻ is an anion of a pharmaceutically acceptableacid, namely the compound of formula (I) in the form enantiomericallyenriched of absolute configuration (R).

[0036] A further subject of the invention described herein is theprocess for the preparation of formula (I) or (II) compounds, usingprocedures which are in themselves known, starting from formula (III)compounds with known nitrating agents, such as, for example,concentrated nitric acid, a nitric acid/sulphuric acid mixture, a nitricacid/acetic anhydride mixture, etc., when T is a hydroxy group or when Tis a good leaving group; or by means of treatment with alkalinenitrates, earth-alkaline nitrates, silver nitrate, ammonium nitrate ortetra-alkylammonium nitrate, when T is a good leaving group, such as,for example, an OSO₂Z group, where Z is as defined above.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The process is illustrated in the following scheme:

[0038] where T is a hydroxy group or T is a leaving group, X₁ ⁻, equalto or different from X⁻, being included in the meanings illustratedabove.

[0039] The X⁻ group, as required and using techniques in themselvesknown, such as the use of ion-exchange resins or by means ofelectrodialysis, can be varied in the context of the possibilitieslisted above, subsequent to treatment with the nitrating system.

[0040] Formula (III) products are optically active and, according to thenitrating system used, formula (I) products can be obtained, with thesame absolute configuration as the formula (III) products or with theopposite absolute configuration, and, to be precise, retention ofabsolute configuration occurs when the nitrating agent used in thecourse of the reaction does not involve the formation of a bond with theasymmetric carbon atom, while inversion of configuration is observedwhen using nitrating agents whose mechanism of action involves an S_(N)2nucleophilic substitution reaction with substitution of the T group.

[0041] A further subject of the invention described herein is the use offormula (I) compounds, and particularly of derivatives with Y equal toan OH group and X⁻ equal to NO₃ ⁻, Cl⁻, OSO₂Z⁻ or OCOZ⁻ with Z equal toC₁-C₁₀ alkyl, or of the formula (II) compound, preferably in theoptically active form of absolute configuration (R) and in the case ofenantiomerically enriched mixtures, said mixtures preferably comprisingan amount of the enantiomer (R) higher than 95%, as pharmaceuticallyactive anti-angina ingredients in solid and liquid pharmaceuticalcompositions for oral administration, parenteral administration,transdermal use or sublingual use in the treatment of ischaemic heartdisease.

[0042] Said compositions include a pharmaceutically effective dose ofthe active ingredient, optionally in mixtures with pharmaceuticallyacceptable vehicles or excipients. The invention described herein alsorelates to a therapeutic method for the treatment of angina pectoris andof various ischaemic forms, comprising the administration of saidcompositions in amounts corresponding to 1-200 mg of active ingredientper day orally, of 0. 1-100 mg of active ingredient per dayparenterally, or of equivalent effective daily doses of activeingredient sublingually or transdermally, preferably 0.1-200 mg ofactive ingredient per day sublingually, and 0. 1-100 mg of activeingredient per day transdermally.

[0043] A further aspect of the invention described herein is a processfor producing (R)-carnitine on an industrial scale starting from thecorresponding (S) enantiomorph, which is a raw material available inlarge amounts and at low cost, in that it is easily obtainable as aby-product of industrial processes of resolution of the racemic mixtureof (R,S)-carnitine or (R,S)-carnitinamide with optically active acidssuch as tartaric acid, tartaric dibenzoyl acid, camphoric acid orcamphorsulphonic acid, by means of the formation of derivatives ofgeneral formula (I) or (II).

[0044] A number of processes have recently been described for theproduction of (R)-carnitine starting from the corresponding (S)enantiomer; in particular, in U.S. Pat. Nos. 5,412,113 and 5,599,978 (S)carnitine is esterified to protect the carboxylic group; the ester thusobtained is then converted to the corresponding mesylate andsubsequently subjected to hydrolysis to restore the carboxylic group; ata suitable pH value, a chiral lactone is formed which presents thedesired (R) configuration which then yields (R)-carnitine by basichydrolysis. This process, however, is not free of drawbacks, owing bothto the fact that one has to protect and then deprotect the carboxylicfunction and because for formation of the mesylate to take place withgood yields an excess of methane sulphonic anhydride has to be used withconsequent formation of large amounts of methane sulphonic acid as aby-product, as well as because the formation of fairly large amounts ofcrotonoylbetaine as a by-product is possible.

[0045] In contrast, the process according to the present invention,which uses formula (I) derivatives, and preferably the one with Y=OH andX⁻=NO₃ ⁻, of absolute configuration (S), or the formula (II) compound ofabsolute configuration (S), easily obtainable starting from(S)-carnitine by treatment with acid nitrating mixtures, makes itpossible to obtain (R)-carnitine, in a very simple manner, with a lowernumber of steps, a high yield and high stereospecificity, by treatmentwith inorganic and organic bases of the aforementioned formula (I) o(II) products in water or in mixtures of water and organic solventmixable in water, operating at a pH value ranging from 7 to 10, andpreferably at a pH value ranging from 7.5 to 9.5. and even morepreferably from 8 to 9 and at a temperature of 50-100° C. and preferablyat a temperature of 60-80° C. This process may occur even withoutisolation of the (I) or (II) derivatives and thus allow “one pot”transformation of (S)-carnitine to (R)-carnitine. The preferred basesare bicarbonates of alkaline or alkaline-earth metals and potassiumphthalimide.

[0046] Though of less industrial interest at this time, the inverseprocess for transforming (R)-carnitine into (S)-carnitine is obviouslyfeasible with the same process.

[0047] A further aspect of the invention described herein is the processfor preparing (R)-carnitine from (S)-carnitine or vice versa through theuse of the formula (IV) intermediate enantiomerically enriched ofabsolute configuration (R) and (S), respectively, prepared in any wayand preferably starting from a formula (I) derivative with Y=OR or NR¹R²with R=H, C₁-C₁₀ alkyl, or substituted alkyl and where R¹R², equal ordifferent from one another, are alkyl, hydrogen R¹R2 and X⁻=NO₃ ⁻ bytreatment with organic or inorganic bases in water or in mixtures ofwater and organic solvent mixable with water.

[0048] The following examples further illustrate the invention.

EXAMPLE 1

[0049] Preparation of (R)-3-Nitriloxy-Carnitine Nitrate

[0050] A solution of (R)-carnitine (20 g; e.e.>99%),) in 65% nitric acid(178 g), cooled to 0-5° C., is slowly added with 98% acetic anhydride(652.2 g) in the space of 12 h. On completing the addition, the mixtureis brought back up to room temperature and maintained under stirring fora further 6 h and then diluted with isopropyl ether (0.6 ), with theformation, in the space of 1-2 h, of a white solid which is filtered,washed with isopropyl ether and dried to yield (R)-3-nitriloxy-carnitinenitrate (27.8 g; yield 83%), with a melting point of 125.5-127° C. androtatory power [α]_(D) ²⁵=−34.66, [α]_(D) ²⁰=−36.7 (c=10%, H₂O). ¹H-NMRspectrum (D₂O)δ5.85-6.00 [m, 1H, —CH(ONO₂)^(−];) 3.75-4.05 [m, 2H, —CH₂—N⁺(CH₃)₃)]; 3.25 [s, 9H,N⁺(CH ₃)₃)]; 2.85-3.20 [m, 2H, —CH ₂—COOH] inppm.

[0051] Elemental analysis: C 30.98; H 5.41; N 15.38.

EXAMPLE 2

[0052] Preparation of (R)-3-Nitriloxy-Carnitine Nitrate

[0053] A solution of (R)-carnitine (20 g; e.e.>99%) in 65% nitric acid(88 g), cooled to 5° C., is slowly added with 98% acetic anhydride (200g) in the space of 2 h. On completing the addition, the mixture ismaintained at 5-10° C. for 3.5 h. After a work-up similar to that in theprevious example, (R)-3-nitriloxy-carnitine nitrate was obtained (26.8g; yield 80%)

EXAMPLE 3

[0054] Preparation of (R)-3-Nitriloxy-Carnitine Nitrate

[0055] The preparation is done as in example 1, but, at the end of thereaction, most of the excess HNO₃ and acetic acid is distilled off atreduced pressure (10 mm Hg).

[0056] The residue is then precipitated by addition of ethyl acetate(0.4) to obtain (R)-3-nitriloxy-carnitine nitrate with comparablecharacteristics.

EXAMPLE 4

[0057] Preparation of (S)-3-Nitriloxy-Carnitine Nitrate A solution of(S)-carnitine (1 g; e.e.>99%) in 65% nitric acid (8.9 g), cooled to 0-5°C., is slowly added with 98% acetic anhydride (27.3 g) in the space of 1h. On completing the addition, the mixture is brought back up to roomtemperature and maintained under stirring for a further 6 h and thendiluted with ethyl ether (75 ml), with the formation, in the space of 2h, of a white solid that is filtered, washed with ether and dried toyield (S)-3-nitriloxy- carnitine nitrate (1.33 g; yield 80%), with amelting point of 125.5-127° C. and rotatory power [α]_(D)²⁵=+34.97(c=10% H₂O).

EXAMPLE 5

[0058] Preparation of (R)-Carnitine

[0059] A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtainedaccording to the process in example 4, in water (20 ml) is added withNaHCO₃ (0.62 g) and heated to 60° C. for 66 h. The complete quantitativeconversion of the starting product to (R)-carnitine nitrate is obtained,with e.e.>99%. The product thus obtained in aqueous solution wasconverted to the inner salt by treatment with ion-exchange resins; bysubsequent concentration of the aqueous solution and crystallisation,0.8 g of (R)-carnitine was obtained with. rotatory power [α]_(D)²⁵=−30.5 (c=10% H₂O).

EXAMPLE 6

[0060] Preparation of (R)-Carnitine

[0061] Operating as in example 5, but working at 80° C., the reaction iscomplete after 8 h.

EXAMPLE 7

[0062] Preparation of (R)-Carnitine

[0063] A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtainedaccording to the process in example 4, in water (20 ml) is added withNaHCO₃ (0.62 g) and heated to 60° C. for 66 h. The complete quantitativeconversion of the starting product to (R)-carnitine nitrate is obtained,with e.e. >99%. The product thus obtained in aqueous solution wasconverted to the inner salt by electrodialysis; by subsequentconcentration of the aqueous solution and crystallisation, 0.7 g of(R)-carnitine were obtained with rotatory power [α]_(D) ²⁵=−30.1(c=10%H₂O).

EXAMPLE 8

[0064] Preparation of (S)-Nitriloxy-Carnitine Nitrate

[0065] 65% nitric acid (150 g) is anhydrified by addition of AC₂O at 5°C. (297.7 g). Again at 5° C., (S)-carnitine inner salt (50 g) and moreacetic anhydride (31.5 g) are added in sequence. On completing theadditions, the reaction is left to proceed at room temperature for 17 hand the excess nitric acid is then distilled at reduced pressure (20 mmHg). The residue is precipitated by addition of EtOAc (1.2) obtaining(S)-3-nitriloxy-carnitine nitrate (66.8 g; yield 80%).

EXAMPLE 9

[0066] Preparation of (S)-Nitriloxy-Carnitine Nitrate

[0067] 65% nitric acid (150 g) is anhydrified by addition of Ac₂O at 5°C. (300 g; 3.1 moles). Again at 5° C., (S)-carnitine inner salt (100 g;0.62 moles) and more acetic anhydride (63 g) are added in sequence. Thecooling is then removed and, after 18 h at room temperature, the residueis precipitated with ethyl acetate (2.4) to obtain(S)-3-nitriloxy-carnitine nitrate (134 g ; yield 80.5%).

EXAMPLE 10

[0068] Preparation of (S)-Nitriloxy-Carnitine Nitrate

[0069] A solution of (S)-carnitine inner salt (100 g) in 90% HNO₃ (215g) is slowly added with AC₂O (187.5 g), maintaining the temperaturebetween 5 and 10° C.

[0070] On completing the addition, the reaction is left to proceed at5-10° C.

[0071] After 2 h the excess nitric acid is evaporated as in example 8and the residue precipitated with ethyl acetate (2.4) to obtain(S)-3-nitriloxy-carnitine nitrate (136 g; yield 81.4%).

EXAMPLE 11

[0072] Preparation of (R)-Carnitine Via the β-Lactone Intermediate

[0073] A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtainedaccording to the process in example 4, in water (20 ml) is added withNaHCO₃ (0.31 g) and heated to 45° C.

[0074] After 48 h the formation of γ-lactone nitrate is noted.

[0075]¹H-NMR (D₂O)=5.25-5.35 (m, 1H), 3.98-3.86 (m, 3H), 3.55-3.45 (dd,1H), 3.24 (s, 9H).

[0076] By treating with an amount of 0.31 g of NaHCO₃ and heating to 80°C., (R)-carnitine having an enantiomeric excess higher than 98% isobtained.

EXAMPLE 12

[0077] Preparation of (R)-Carnitine Without Isolation of(R)-Nitriloxy-Carnitine

[0078] Operating as in example 9, but distilling the crude product inthe end to remove the nitric acid and most of the acetic acid, insteadof precipitating (S)-nitriloxy-carnitine and adding KHCO₃ (257 g)directly to the residue suitably diluted with H20 (3.3), the completeformation of (R)-carnitine nitrate is obtained by working for 8 h at 80°C.

[0079] The product thus obtained in aqueous solution was converted tothe inner salt by means of treatment with ion-exchange resins; bysubsequent concentration of the aqueous solution and crystallisation, 82g of (R)-carnitine were obtained with rotatory power [α]_(D) ²⁵=−28.5(c=10% H₂O).

EXAMPLE 13

[0080] Preparation of (R)-Carnitine Without Isolation of(R)-Nitriloxy-Carnitine

[0081] To a mixture of (S)-carnitine inner salt (100 g; 0.62 moles) inglacial CH₃COOH (100 g) 100% HNO₃ is added (117.2 g; 1.86 moles) keepingthe temperature at 10° C. and in the space of 1 hour and 5 minutes.Then, the temperature was lowered to 0-5° C. and acetic anhydride wasadded (76 g; 0.744 moles) in 2 hours and 10 minutes. After keeping thereaction mixture at cool (3-5° C.) for further 3 hours from the end ofaddition, the reaction mass was left at 5° C. overnight. The followingmorning, temperature was left to rise up to 19° C. and ethyl acetate wasadded (835 ml) to precipitate nitriloxy-carnitine nitrate. Afterstirring the suspension for 30′, it was filtered washing with ethylacetate (330 ml). The wet solid on the filter (164,6 g) was dissolved inwater (760 ml) and NaHCO₃ (94.53 g; 1.125 moles) was added to thesolution. Temperature was kept at 80° C. for 9 hours, the solution wasdiluted with water (760 ml) and passed through IR 120 (H⁺) (1320 ml)with the purpose to block carnitine. After washing with water, tocompletely eliminate acidity, elution was made with 1N NH₃ and theammonia solution was concentrated and eliminated with an azeotrope withisobutyl alcohol, giving (R)-carnitine inner salt, having anenantiomeric excess higher than 98% (70.8 g; yield 70.2%).

EXAMPLE 14

[0082] Preparation of (R)-Carnitine Via the β-Lactone Intermediate

[0083] A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtainedaccording to the method of example 4, in N-methyl pyrrolidone (20ml) wasadded with potassium phthalimide (0.825 g; 0.00446 moles) After 20h theformation of the β-lactone nitrate was observed.

[0084]¹H-NMR (D₂O)=5.25-5.35 (m, 1H), 3.98-3.86 (m, 3H), 3.55-3.45 (dd,1H), 3.24 (s, 9H).

1. Formula (I) compounds in optically active form with absoluteconfiguration (R) or (S)

where Y is an OR or NR¹R² group with R equal to hydrogen, C₁-C₁₀ all oralkyl substituted with C₆-C₁₀ aryl, said aryl optionally carrying one ormore C₁-C₄ alkyls; R¹ and R², equal or different from one another, arehydrogen, C₁-C₁₀ alkyl or alkyl substituted with C₆-C₁₀ aryl, said aryloptionally carrying one or more C₁-C₄ aryls; or, taken together, form a5-7 atom heterocyclic ring with the nitrogen atom; or Y is the residueof an esterified polyalcohol with at least one nitric acid equivalent;X⁻ is the anion of a pharmaceutically acceptable organic or inorganicacid, or, if Y is an OH group, the formula (I) product may exist in theform of an inner salt, i.e. with formula (II)

and their enantiomerically enriched mixtures.
 2. Compounds according toclaim 1, whose absolute configuration is (R).
 3. Compounds according toclaims 1 or 2, which X⁻ is selected from the group consisting of N_(O) ₃⁻, Cl⁻, Br⁻, I⁻, HSO₄ ⁻, (SO₄ ⁻⁻)_(0,5), H₂PO₄ ⁻, (HPO₄ ²⁻)_(0,5), (PO₄³⁻⁾ _(0,33), a residue of a hydroxy acid, a residue of a bicarboxylicacid, OSO₂Z⁻, OCOZ⁻or OCOH⁻with Z equal to C₁-C₁₀ alkyl, alkylsubstituted with one or more halogen atoms, C₆-C₁₀ aryl, said aryloptionally being substituted with one or more halogen atoms, C₁-C₄ alkylgroup, or C₁-C₄ alkoxy.
 4. Compounds according to claim 3, in which X⁻is selected from the group consisting of mandelate, orotate, acidaspartate, acid citrate, fumarate and acid fumarate, lactate, maleateand acid maleate, mucate, glucose phosphate, tartrate and acid tartrate,succinate, acid succinate, oxalate, malate and acid malate.
 5. Compoundsaccording to claim 3, in which X⁻ is an anion of a pharmaceuticallyacceptable salt.
 6. Process for the preparation of compounds accordingto claims 1-5, comprising the treatment of a formula (III) compound witha nitrating agent not involving the formation of a bond with theasymmetric carbon atom according to the following scheme:

where T is an hydroxy group or T is a leaving group, X₁ ⁻, equal to ordifferent from X⁻, being included among the meanings illustrated above,to yield the formula (I) compound with the same absolute configurationas the formula (III) compound.
 7. Process according to claim 6, in whichsaid nitrating agents are selected from the group consisting of:concentrated nitric acid, a mixture of nitric acid and sulphuric acid, amixture of nitric acid and acetic anhydride.
 8. Process for thepreparation of compounds according to claims 1-5, comprising thetreatment of a formula (III) compound with a nitrating agent whosemechanism of action involves an SN2 nucleophilic substitution reactionwith substitution of the T group.
 9. Process according to claim 8, inwhich said nitrating agents are selected from the group consisting of:alkaline nitrates, alkaline-earth nitrates, silver nitrate, ammoniumnitrate or tetra-alkylammonium nitrate.
 10. Process according to claim8, in which the T group is an OSO₂Z group, where Z is as defined above.11. Process according to any of claims 6-10, in which the X⁻ group, ifrequired, may be varied in the context of the possibilities listedabove, subsequent to treatment with the nitrating system.
 12. Processaccording to claim 11, in which the variation of the X⁻ group is done bymeans of ion-exchange resins or by means of electrodialysis.
 13. Use ofthe compounds according to claims 1-5 as medicaments.
 14. Use accordingto claim 13, in which the absolute configuration is (R).
 15. Useaccording to claim 14, in which the enantiomerically enriched mixturecomprises a content of (R) enantiomer higher than 95%.
 16. Use of thecompounds according to claims 1-5 for the preparation of medicinesuseful for the treatment of angina.
 17. Use of the compounds accordingto claims 1-5 for the preparation of medicaments useful for thetreatment of ischaemic forms.
 18. Pharmaceutical compositions containinga pharmaceutically effective dose of at least one compound according toclaims 1-5, in a mixture with pharmaceutically acceptable vehiclesand/or excipients.
 19. Pharmaceutical compositions according to claim 18in solid and liquid form for oral, parenteral, transdermal or sublingualadministration.
 20. Process for the preparation of (R)-carnitinestarting from the corresponding enantiomer (S) of the compoundsaccording to claim 1, comprising treatment of said compounds withdiluted bases.
 21. Process according to claim 20, where X⁻ is thenitrate ion and Y is OH.
 22. Process according to claims 20 or 21, wheresaid diluted base is sodium bicarbonate.
 23. Process according to any ofclaims 20-22, where said base is diluted in water or in mixtures ofwater and organic solvent mixable with water.
 24. Process according toany of claims 20-23, where the pH ranges from 7 to
 10. 25. Processaccording to any of claims 20-24, where the reaction temperature rangesfrom 50 to 100° C.
 26. Process for the preparation of (R)-carnitine,comprising the following steps: a) treatment of a formula (III)enantiomer of absolute configuration (S), as described in claims 6-7,with a nitrating agent not involving the formation of a bond with theasymmetric carbon atom, to yield the formula (I) compound with the sameabsolute configuration as the formula (III) compound; b) treatment ofthe formula (I) compound with diluted bases, according to the processdescribed in claims 20-25.
 27. Process for the preparation of(R)-carnitine, comprising the following steps: a) treatment of a formula(III) enantiomer of configuration (R), as described in claims 8-9, witha nitrating agent whose mechanism of action involves an S_(N)2nucleophilic substitution reaction with substitution of the T group toyield the formula (I) compound with the opposite absolute configurationto the formula (III) compound; b) treatment of the formula (I) compoundwith diluted bases according to the process described in claims 20-25.28. Process according to claims 26 or 27, carried out without isolationof the formula (I) compound.
 29. Process for the preparation of(S)-carnitine, comprising the following steps: a) treatment of a formula(III) enantiomer of absolute configuration (R), as described in claim 1,with a nitrating agent not involving the formation of a bond with theasymmetric carbon atom, to yield the formula (I) compound with the sameabsolute configuration as the formula (III) compound, as described inclaims 6-7 and 11-12; b) treatment of the formula (I) compound withdiluted bases, according to the process described in claims 20-25. 30.Process for the preparation of (S)-carnitine, comprising the followingsteps: a) treatment of a formula (III) enantiomer of configuration (S),as described in claim 1, with a nitrating agent whose mechanism ofaction involves an S_(N)2 nucleophilic substitution reaction withsubstitution of the T group to yield the formula (I) compound with theopposite absolute configuration to the formula (III) compound asdescribed in claims 8-12; b) treatment of the formula (I) compound withdiluted bases according to the process described in claims 20-25. 31.Formula (I) or (II) compound as described in claim 1, as an intermediatein the process of claims 20-30.
 32. Process for the preparation of(R)-carnitine from (S)-carnitine or vice versa comprising treatment ofthe formula (IV) compound, enantiomerically enriched of, respectively,absolute configuration (R) or (S)

comprising treatment of said compounds with diluted bases as describedin claims 20-25.
 33. Process for the preparation of (R)-carnitine from(S)-carnitine or vice versa comprising: a) transformation of the formula(I) compound, described in claim 1, in which Y=OR or NR¹R², with R=H,C₁-C₁₀ alkyl, or substituted alkyl and where R¹R², equal or differentfrom one another, are hydrogen, C₁-C₁₀ alkyl and X⁻=NO₃ ⁻, into theformula (IV) compound, enantiomerically enriched of, respectively,absolute configuration (R) or (S):

b) with organic or inorganic bases in water or water and organic solventmixable with water, as described in claims 20-25.
 34. Process accordingto claims 32 or 33, wherein the nitrate anion of the final product isconverted in a X⁻ anion as defined in claim
 1. 35. Process according toclaim 34, as disclosed in claim
 12. 36. Use of compound of formula (IV)

as intermediate in the process of claims 33-34.